Inhibitors of polyamine metabolism

review article

Alison Fraser, Heather Mann Wallace

Research output: Contribution to journalArticle

115 Citations (Scopus)

Abstract

The identification of increased polyamine concentrations in a variety of diseases from cancer and psoriasis to parasitic infections has led to the hypothesis that manipulation of polyamine metabolism is a realistic target for therapeutic or preventative intervention in the treatment of certain diseases.

The early development of polyamine biosynthetic single enzyme inhibitors such as alpha-difluoromethylornithine (DFMO) and methylglyoxal bis(guanylhydrazone) showed some interesting early promise as anticancer drugs, but ultimately failed in vivo. Despite this, DFMO is currently in use as an effective anti-parasitic agent and has recently also been shown to have further potential as a chemopreventative agent in colorectal cancer.

The initial promise in vitro led to the development and testing of other potential inhibitors of the pathway namely the polyamine analogues. The analogues have met with greater success than the single enzyme inhibitors possibly due to their multiple targets. These include down regulation of polyamine biosynthesis through inhibition of ornithine decarboxylase and S-adenosylmethionine decarboxylase and decreased polyamine uptake. This coupled with increased activity of the catabolic enzymes, polyamine oxidase and spermidine/spermine N-1-acetyltransferase, and increased polyamine export has made the analogues more effective in depleting polyamine pools. Recently, the identification of a new oxidase (PAO-h1/SMO) in polyamine catabolism and evidence of induction of both PAO and PAO-h1/SMO in response to polyamine analogue treatment, suggests the analogues may become an important part of future chemotherapeutic and/or chemopreventative regimens.

Original languageEnglish
Pages (from-to)353-365
Number of pages13
JournalAmino Acids
Volume26
Issue number4
DOIs
Publication statusPublished - Jul 2004

Keywords

  • polyamines
  • putrescine
  • spermidine
  • spermine
  • cancer
  • apoptosis
  • analogues
  • enzyme inhibitors
  • difluoromethylornithine disease
  • S-adenosylmethionine decarboxylase
  • L-methionine decarboxylase
  • trypanosoma-brucei-brucei
  • murine leukemia-cells
  • human cancer-cells
  • ornithine-decarboxylase
  • alpha-difluoromethylornithine
  • methylglyoxal bis(guanylhydrazone)
  • irreversible inhibition
  • biosynthesis inhibitor

Cite this

Inhibitors of polyamine metabolism : review article. / Fraser, Alison; Wallace, Heather Mann.

In: Amino Acids, Vol. 26, No. 4, 07.2004, p. 353-365.

Research output: Contribution to journalArticle

Fraser, Alison ; Wallace, Heather Mann. / Inhibitors of polyamine metabolism : review article. In: Amino Acids. 2004 ; Vol. 26, No. 4. pp. 353-365.
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AB - The identification of increased polyamine concentrations in a variety of diseases from cancer and psoriasis to parasitic infections has led to the hypothesis that manipulation of polyamine metabolism is a realistic target for therapeutic or preventative intervention in the treatment of certain diseases.The early development of polyamine biosynthetic single enzyme inhibitors such as alpha-difluoromethylornithine (DFMO) and methylglyoxal bis(guanylhydrazone) showed some interesting early promise as anticancer drugs, but ultimately failed in vivo. Despite this, DFMO is currently in use as an effective anti-parasitic agent and has recently also been shown to have further potential as a chemopreventative agent in colorectal cancer.The initial promise in vitro led to the development and testing of other potential inhibitors of the pathway namely the polyamine analogues. The analogues have met with greater success than the single enzyme inhibitors possibly due to their multiple targets. These include down regulation of polyamine biosynthesis through inhibition of ornithine decarboxylase and S-adenosylmethionine decarboxylase and decreased polyamine uptake. This coupled with increased activity of the catabolic enzymes, polyamine oxidase and spermidine/spermine N-1-acetyltransferase, and increased polyamine export has made the analogues more effective in depleting polyamine pools. Recently, the identification of a new oxidase (PAO-h1/SMO) in polyamine catabolism and evidence of induction of both PAO and PAO-h1/SMO in response to polyamine analogue treatment, suggests the analogues may become an important part of future chemotherapeutic and/or chemopreventative regimens.

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KW - putrescine

KW - spermidine

KW - spermine

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KW - trypanosoma-brucei-brucei

KW - murine leukemia-cells

KW - human cancer-cells

KW - ornithine-decarboxylase

KW - alpha-difluoromethylornithine

KW - methylglyoxal bis(guanylhydrazone)

KW - irreversible inhibition

KW - biosynthesis inhibitor

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DO - 10.1007/s00726-004-0092-6

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SP - 353

EP - 365

JO - Amino Acids

JF - Amino Acids

SN - 0939-4451

IS - 4

ER -